3-aminoalkyloxyindoles

ABSTRACT

This invention is concerned with novel and pharmaceutically active indole derivatives having the structure:   AND THE SALTS THEREOF WITH PHYSIOLOGICALLY ACCEPTABLE ACIDS, IN WHICH EACH OF X and Y is selected from the group consisting of hydrogen, hydroxy, lower alkyl having 1-3 carbon atoms and lower alkoxy having 1-3 carbon atoms, R1 is selected from the group consisting of hydrogen, lower alkyl having 1-4 carbon atoms and benzyl, R2 is selected from the group consisting of hydrogen, lower alkyl having 1-4 carbon atoms, benzyl and phenyl, R3 is selected from the group consisting of hydrogen, lower alkyl having 1-8 carbon atoms, cycloalkyl having 5 or 6 carbon atoms, benzyl and 2-phenylethyl, and A is a straight or branched alkylene chain containing from 2 to 4 carbon atoms.

United States Patent [191 Lundt 51 Jan. 14,1975

[ 3-AMINOALKYLOXYINDOLES [75] Inventor: Behrend Friedrich Lundt, Lyngby,

Denmark.

[73] Assignee: Novo Terapeutisk Laboratorium A/S, Bagsvaerd, Denmark[22] Filed: Nov. 10, 1972 [21] Appl. No.: 305,239

Related U.S. Application Data [63] Continuation-in-part of Ser. Nos.39,863, May 22, 1970, abandoned, and Ser. No. 201,550, May 20, 1970, andSer. No. 287,311, Sept. 8, 1972.

[30] Foreign Application Priority Data May 27, 1970 Great Britain26683/70 [52] U.S. Cl..... 260/326.l5, 260/326.11 R, 424/274 [51] Int.Cl C07d 27/56 [58] Field of Search 260/326.15

[56] References Cited UNITED STATES PATENTS 3,703,524 11/1972Braendstroem et al 260/293.6l

Primary Examiner-Joseph A. Narcavage Attorney, Agent, or FirmSynnestvedt& Lechner 57 7 ABSTRACT This invention is concerned with novel andpharmaceutically active indole derivatives having the structure:

R is selected from the .group consisting of hydrogen, lower alkyl havingl-8 carbon atoms, cycloalkyl having 5 or 6 carbon atoms, benzyl and2-phenylethyl, and A is a straight or branched alkylene chain containingfrom 2 to 4 carbon atoms.

10 Claims, No Drawings 1 g-AMINQALKYLOXYINDOLES in which:

each of X and Y is selected from the group consisting of hydrogen;hydroxy; lower alkyl having 13 carbon atoms and lower alkoxy having l-3carbon atoms,

R is selected from the group consisting of hydrogen;

lower alkyl having 1-4 carbon atoms and benzyl,

R is selected from the group consisting of hydrogen; lower alkyl havingl-4 carbon atoms; benzyl and phenyl,

R is selected from the group consisting of hydrogen; lower alkyl having1-8 carbon atoms; cycloalkyl having 5 or 6 carbon atoms; benzyl and2-phenylethyl, and

A is a straight or branched alkylene chain containing from 2 to 4 carbonatoms,

and salts of the said compounds of formula I with physiologicallyacceptable acids.

Examples of acids which are able to form physiologically tolerable saltswith indole derivatives of the above formula are inorganic acids such ashydrochloric acid, sulfuric acid and phosphoric acid, as well as organicacids such as acetic acid, tartaric acid,-citric acid, oxalic acid,fumaric acid and maleic acid.

The novel indole derivatives of the above formula (1) and their acidaddition salts may according to the invention be prepared in one or moreof the following manners:

a. Compounds of the general formula (I) in which X, Y, A, R, R and R areas defined in connection with formula (I) may be prepared byhydrogenolysis of the corresponding compounds of the general formula:

in which: each of the substituents X and Y is selected from the groupconsisting of hydrogen; benzyloxy; lower alkyl having 1-3 carbon atomsand'lower alkoxy having l-3 carbon atoms, A, R, R and R are as definedabove, and R represents benzyl.

The particular compounds of the general formula (I) in which Rrepresents benzyl may be prepared by partially hydrogenolysing thecorresponding compounds of the general formula (11) in which R and R arebenzyl. 5 The said hydrogenolysis is performed in a solvent, such asethanol, in the presence of a suitable catalyst, e.g,, palladium oncarbon, or

b, Compounds of the general formula (1) in which X, Y, A, R, R and R areas indicated in connection with formula (I), excluding, however,compounds in which R represents hydrogen, may be prepared by convertingunder suitable hydrogenolytic conditions indole derivatives of thegeneral formula 11, in which,

X, Y, R, R and A are as defined in connection with formula (11), andeach of R and R" is selected from the group consisting of hydrogen andbenzyl,

in the presence of the particular aldehyde or ketone selected as aprecursor, in a reductive alkylation process, of the substitutent R Thereaction is performed in a solvent such as ethanol in the presence ofhydrogen and a suitable catalyst such as palladium on carbon, or 1 c.Compounds of the general formula (1) in which X, Y and A, R, R and R areas defined in connection with formula (1), excluding, however, compoundsin which R represents hydrogen, may be prepared by reacting in asuitable solvent, e.g., methanol or tetrahydrofuran, indole derivativesof the general formula:

in which X, Y, R, R and A-are as defined above with. the particularaldehyde or. ketone selected as a precursor, in a reductive alkylationprocess, of the substituent R followed by treatment of the reactionmixture with a suitable reductive agent, e.g., sodium borohydride,whereafter, if desired, the indole derivatives thus prepared may beconverted into salts with physiologically acceptable acids. The acidadditionsalts are prepared by reacting the base form of the indolederivatives with no less than one equivalent of the appropriate acid inan organic solvent such as ethanol or isopropanol. Such salts mayadvantageously be used for the purpose of isolating and/or purifying thecompounds of this invention, and may be transformed in a manner known,per se, into the corresponding salts with other physiologicallyacceptable acids.

The present invention also provides processes analogous to thosedescribed and claimed in the said U.S.

pat. application Sen No. 39,863 for preparing the novel intermediaryindole derivatives of the general formula (11) in which X, Y, A, R, R Rand R are as defined in connection with formula (11) excluding, however,compounds in which R represents hydrogen.

The first step comprises condensing indoxyl derivatives of the generalformula:

COCH

in which X, Y and R are as defined above, with compounds of the generalformula:

acids exhibit valuable pharmacological properties and are thus ofpotential utility in human therapy, particularly as analgetic andantiinflammatory agents.

Thus, formula I indole derivatives have been found to hydrochloride 2 R5 exhibit, in varying degrees, anti-inflammatory activity X A N 3 (V)when evaluated by various standard pharmacological 8 tests involvingboth oral and parenteral administration to animals. For example, in onesuch test pedal inflamin which A, R and R are as defined above, and Xrepmation was induced in rats by Carrageenin according resents a halogenatom or agroup functionally equiva- 10 to thfi {method of wlmher (itill, lent therewith, thus producing a compound of the gen- E P 1 (1962)P- 544); and the era] formula: inflammatoryactivity was expressed interms of per cent inhibition of pedal inflammation. Antl- L inflammatoryvalues for a number of formula I indole O A I l5 derivativesadministered orally are presented in Table 3 l. R Furthermore, indolederivatives of the present inven- 1 2 (VI) tion exhibit, in varyingdegrees, an additional analgetie Y N B effect. Many of the formula Iindole compounds exhibit I both anti-inflammatory and analgetic activityand (,OCH3 therefore may be particularly suited for the treatment ofinflammatory conditions accompanied by pain. in which X', Y, A, R R andR are as defined above. g i i i gs f g g g g i The reaction is performedin a suitable solvent, such as p 1 y e bmqns m i pharmacological testsperformed in a variety of animal dimethylformamide or dimethylsulfoxlde1n the presspecies. For example, the analgetlc activity was exam enee ofan acid-binding agent such as potassium earmed after subcutaneousadministration to mice in the bonate or sodium hydride. I

The intermediates of the general formula (II) in tail-clip testaccording to F. Haftner (Dcutsche Mcd. h R1 t h d d Wochenschrift, 55(1929), p. 731). The analgctrc acrhepresen.s roggtn prepare g i gtivity, in terms of ED -values, of a number of formula S 6p T J .eaceconipoun S 6 l indole derivatives, is presented in Table ll. genira I gm a g 9 vent Sue f as An overall evaluation of the data from the various:3 am) ano a; l lg agent pre standard animal tests using these novelindole derivaa y ammoma or l a a meta OX1 f; h I tives reflects a widespectrum of anti-inflammatory ac For the preiparatlon mte rmedlates O te genera tivity and/or analgetic activity and indicates that the fofmulap In whlch, R ls dlfffirem m hydrogen a compounds of this invention mayhave valuable and adthird step is added which comprises reacting thedeacevantageous therapeutic properties as Compared m thc tylated Compounds Produced the Second Step above anti-inflammatory agents andanalgetic agents that are with an alkylatmg agent of the generalformula: Widely used at he present mm X3 R5 40 However, for reasons ofsafety of administration, the preferred formula I indole derivatives arethose which (Vll) exhibit anti-inflammatory activity and/or analgeticac- I tivity when administered to mammals at a dosage level Whlch X3 15halogen atom and l Selected from below that of the LD -value of thatparticular comthe group consisting of lower alkyl having 1-4 C-atomspound. and y t All of the compounds in Table l exhibit very pro- TheT636110" Performed a sultable Solvent Such nounced anti-inflammatoryactivity at dosage levels sigas dimethylformamide or toluene, in thepresence of an ifi tl b l their LDwvaiuex acid binding agent, Such asSodium y All of the compounds in Table ll exhibit very pro- The novelindole denvatlves of the gene1'al formula pounced analgetic activity atdosage levels significantly (l) as well as their salts withphysiologically acceptable below h i LD 1 Table l Anti-inflammatoryeffect: Compound inhibition I00 mg/kg orally 3-(3-aminopropoxy)indolehydrochloride 48 3 (2-isopropylamin0ethoxy)indole hydrochloride 663-(2-n-propylaminoethoxy)indole hydrochloride 623-(2-aminoethoxy)-2-methylindole hydrochloride 393-(Z-aminoethoxy)-2-phenylindole 773-(2-isopropylaminoethoxy)-4-methoxyindole hydrochloride 343-(2-isopropylaminoethoxy)-2-phenylindole hydrochloride 79l-benzyl-3-(2-isopropylaminoethoxyl-2-phenylindole hydrochloride 67l-benzyl-3-(2-isopropylaminoethoxy)4-methoxy|ndole l hydrochloride 671-benzyl-3-(2-isopropylaminoethoxy)indole n Table l-ContinuedAnti-inflammatory effect:

Compound inhibition 100 mg/kg orally 3-(Z-aminoethoxy)-5-methylindolehydrogen oxalate l-n-butyl-3-(Z-isopropylaminoethoxy)indolehydrochloride 2-benzyl-3-(2-isopropylaminoethoxy)indole hydrochloride3-(Z-cyelohexylaminoethoxy)-5-methoxyindole hydrochloride 523-(Z-ethylaminoethoxy)indole hydrochloride3-(Z-isopropylaminoethoxy)-5-methoxyindole hydrochloride 50 mg/kg orallyTable II Analgetic effect:

Haffners test mg/kg s.c.

Compound All formula I compounds exhibiting significant antiinflammatoryactivity also possess a measurable, but varying analgetic activity,whereas some formula 1 compounds possess analgetic activity, only.

The group of indole derivatives within the general formula I thatexhibit only analgetic effects are those having the structure and theacid addition salts thereof with physiologically acceptable acids, inwhich R is lower alkyl having 4-7 carbon atoms, benzyl and2-phenylethyl, and A is ethylene.

In addition, many of the compounds in Tables I and II exhibit highdegrees of activity as to both effects.

When the compounds of the present invention are employed as therapeuticagents they may be administered alone or in combination withpharmaceutically acceptable carriers, the proportion of which isdetermined by the solubility and chemical nature of the compound, chosenroute of administration and standard pharmaceutical practice. Forexample, they may be administered orally in the form of tablets orcapsules containing such excipients as starch, milk sugar, certain typesof clay and so forth. They may be administered sublingually in the formof troches or lozenges in which (VIlI) the active ingredient is mixedwith sugar and corn syrups, flavoring agents and dyes; and thendehydrated sufficiently to be pressed into a solid form. They may beadministered orally in the form of solutions which may contain coloringand flavoring agents, or they may be injected parenterally,'that isintramuscularly, intravenously or subcutaneously. For parenteraladministration, they may be used in the form of a sterile solutioncontaining other solutes, for example, enough saline or glucose to makethe solution isotonic.

The dosage of the present therapeutic agents will vary with the route ofadministration and the particular compound chosen. Furthermore, it willvary with the subject under treatment. In general, the compounds of thisinvention are most desirably administered at a concentration level thatwill generally afford effective results without causing any harmful ordeleterious side effects and preferably at a dose level that is in therange of from 5 mg to about 2,000 mg per day, although, in individualcases, division as well as multiplication of doses may be necessary.

The preparation of the novel indole derivatives of the present inventionis illustrated in detail in the following examples.

EXAMPLE I 3-(2-aminoethoxy)indole hydrogen oxalate3-(2-dibenzylaminoethoxy)indole (35.7 g), dissolved in ethanol (400 mlof 99%) was hydrogenolyzed in the presence of palladium/carbon (10 g ofl()%) at 5060 psi and 25C in the course of about l8 hours. The catalystwas filtered off and the filtrate was concentrated in vacuum. Theresidue, dissolved in ethanol (30 ml) was cautiously added to a solutionof oxalic acid (27 g) in ethanol (125 ml). The resulting precipitate wasrecrystallized from aqueous ethanol (75%), yielding3-(2-aminoethoxy)indole hydrogen oxalate (13.6 g, 51% yield)) with mp.134136C. Anal. calcd. for C H O N C, 54.1%; H, 5.3%; N, 10.6%. Found:

C, 54.0%; H, 5.3%; N, 10.6%.

The intermediate, 3-(Z-dibenzylaminoethoxy)indole, was prepared in thefollowing manner:

A mixture of l-acetylindoxyl (17.5 g), 2- dibenzylaminoethyl chloridehydrochloride (44.5 g) and potassium carbonate (62 g) indimethylsulfoxide (DMSO, 200 ml) was left with stirring at 40C for 12hours. The precipitate which formed after the addition of ice-water (1L) was filtered off and recrystallized from ethanol. Alternatively, theprecipitate was extracted with ethyl acetate (2 X 600 ml) followed byconcentration of the ethyl acetate extract. The residue so obtainedyielded after recrystallization from ethanol1-acetyl-3-(2-dibenzy1aminoethoxy)indole (34 g, 85% yield) with mp.105107C.

l-aeetyl-3-(2-dibenzylaminoethyoxy)indole (100 g) was treated for min.with a refluxing solution of sodium ethoxide, prepared from sodium (29g), in ethanol (700 ml of 99%). The reaction mixture was cooled to10-20C and water (1400 ml) was slowly added. The solid material soobtained was recrystallized from a mixture of benzene 100 ml) andisooctane (200 ml), yielding 3-(2-dibenzylaminoethoxy)indole (58 g, 65%yield) with mp. 7576C.

EXAMPLE 2 3-(2-aminoethoxy)-5-methoxyindole 3-(2dibenzylaminoethoxy-S-methoxyindo1e (108 g) was hydrogenolyzed by aprocedure analogous to that described in Example 1. The reactionmixture, freed from the catalyst, was concentrated in vacuum and thecrude 3-(2-aminoethoxy)-5-methoxyindole was recrystallized from toluene(150 ml). The pure compound (40.6 g, 72% yield) had the mp. 103-104C.Anal. calcd. for C H O N C, 64.1%; H, 6.8%; O, 15.5%; N, 13.6%. Found:

C, 63.8%; H, 6.9%; O, 15.7%; N, 13.8%.

The starting material, 3-(Z-dibenzylaminoethoxy)-5- methoxyindole wasprepared in the following manner:

A mixture of 1-aeetyl-5-methoxyindoxyl (75 g), 2- dibenzylaminoethylchloride hydrochloride (163 g) and potassium carbonate (228 g) in DMSO(730 ml) was kept with stirring for 6 hours at 40C. The reaction mixturewas treated with icewater (4 L) and the resulting suspension wasextracted with ethyl acetate (3 X 400 ml). The ethyl acetate extract wasdried and concentrated in vacuum. Recrystallization of the residue fromethanol gave 1-acetyl-3-(2-dibenzylaminoethoxy)-5-methoxyindole (122 g,78% yield) with mp. 8283C. This compound was deacetylated in the mannerdescribed in Example 1. The product, 3-(2-dibenzylaminoethoxy)-5-methoxyindole, was isolated as an oil.

EXAMPLE 3 3-(2-aminoethoxy)-5-hydroxyindole hydrogen oxalate.

starting 5-benzyloxy-3-(2-dibenzylaminoethoxy)indolc was subjected tohydrogenolysis and worked up in the manner described in Example 1, thusaffording 3-(2- aminoethoxy)-5-hydroxyindole hydrogen oxalate with mp.l65-166C in 50% yield.

The starting material, 5-benzyloxy-3-( 2- dibenzylaminoethoxy)indole,was synthesized by aminoalkylation of 1-acetyl-5-benzyl-oxyindoxyl in aprocedure analogous to that described in Example 1 and deacetylation ofthe product was effected as indicated in the same example.5-benzyloxy-3-(2-dibenzylaminoethoxy)indole with mp. 8788C crystallizeddirect from the reaction mixture without addition of water. The overallyield, based on 1-acctyl-5-bcnzyloxyindoxyl, was 68.5%.

EXAMPLE 4 3-(2-aminoethoxy)-5-methy1indole hydrogen oxalate In aprocedure analogous to that of Example 1, but

from 3-(Z-dibenzylaminoethoxy)-5- methylindole,3-(2-aminoethoxy)-5-methylindole hydrogen oxalate with mp. 139140C wasobtained in 35% yield. The crystalline salt contains water of hydrationwhich is retained tenaciously, even after drying in vacuum.

The intermediate, 3-(2dibenzylaminoethoxy)-5- methylindole was preparedin the following manner:

l-acetyl-S-methylindoxyl was aminoalkylated by the procedure describedin Example 2, yielding 1-acetyl-3-(2-dibenzylaminoethoxy)-5-methylindole with mp. 104-105C in 68% yield.

1-acetyl-3-(2-dibenzylaminoe'thoxy))-5- methylindole (32 g), dissolvedin methanol (350 ml) saturated with ammonia was heated in an autoclaveto 60C for 6 hours. The reaction mixture was cooled and concentrated invacuum, leaving a residue which after recrystallization from a mixtureof benzene (60 ml) and isooctane (250 ml) afforded3-(2-dibenzylaminocthoxy)-5-methylindole with mp. 57-58C. The yield was50%.

EXAMPLE 5 3-(3-aminopropoxy)indole hydrochloride A solution of3-(3-dibenzylaminopropoxy)indole hydrochloride in ethanol was subjectedto hydrogenolysis in a manner similar to that of Example 1. The product,3-(3-aminopropoxy)indole hydrochloride, with mp. 176-l78C was obtainedin 41% yield.

3-(3-dibenzylaminopropoxy)indole hydrochloride was synthesized by thefollowing procedure:

A mixture of l-acetylindoxyl (35 g), 3- dibenzylaminopropyl chloridehydrochloride (68.2 g) and potassium carbonate (91 g) in DMSO (400 ml)was left with stirring at 60C for 24 hours. The reaction mixture wastreated with ice-water (1.5 L) and the aqueous suspension was extractedwith ethyl acetate (3 X 500 ml). The ethyl acetate extract was dried andfreed of solvent. Recrystallization from ethanol yielded1-acetyl-3-(3-dibenzy1aminopropoxy)indole (34.5 g, 42% yield).with mp.99l00C.

Sodium (12.8 g) was dissolved in ethanol (290 ml of 99%) and1-acetyl-3-(3-dibenzylaminopropoxy)indolc (46 g) was added. The mixturewas refluxed for 30 minutes, cooled to about 25C and subsequentlytreated with ice-water (1.7 L). The resulting emulsion was extractedwith ethyl acetate (3 X 200 ml). Addition of a solution of hydrogenchloride in ethanol to the dried ethyl acetate phase afforded acrystalline precipitate of 3-(3-dibenzylaminopropoxy)indolehydrochloride (42.5 g, 93.5% yield) with mp. 180-181C.

EXAMPLE 6 3(2-methylaminoethoxy)indole hydrochloride3-(2-(N-benzyl-N-methylamino)ethoxy)indole (10 g), dissolved in ethanol(150 ml of 99%) was hydrogenated in the presence of palladium/carbon (2g of 10%) at 50-60 psi and 25C for 10-18 hours. After removal of thecatalyst, the solution was concentrated in vacuum and the residue wasdissolved in isopropanol (30 ml). Addition of a solution of hydrogenchloride in isopropanol at O5C converted the base into a crystallinehydrochloride. Recrystallization from isopropanol afforded3-(Z-methylaminoethoxy)indole hydrochloride (4.7 g, 70% yield) with mp.140141C.

Anal. calcd. for C H ON Clz C, 58.3%; H, 6.7%; O, 7.1%; N, 12.4%; C1,15.6% Found:

C, 58.0%; H, 7.0%; O, 7.3%; N, 12.4%; C1, 15.5%;

3-(2-(N-benzyl-N-methylamino)ethoxy)indole is prepared by the methoddescribed below:

A mixture of l-acetylindoxyl (17.5 g), Z-(N-benzyl- N-methylamino)ethylchloride hydrochloride (33 g) and potassium carbonate (62 g) wasrefluxed for 48 hours in ethyl acetate (500 ml) containing water (5 ml).After chilling, the reaction mixture was filtered and the filtrate wasconcentrated. The residue so obtained was recrystallized fromisopropanol, affording 1-acetyl-3-(2-(N-benzyl-N-methylamino)ethoxy)indole (22 g, 68% yield) with mp. 7274C.

l-acetyl-3-(Z-(N-benzyl-N- methylamino)ethoxy)indole was deacetylatedaccording to the procedure described in Example 4. The product,3-(2-(N-benzyl-N-methylamino)ethoxy)indole, was isolated as an oil.

EXAMPLE 7 3-(2-benzylaminoethoxy)indole hydrochloride3-(2-dibenzylaminoethoxy)indole (7.1 g, 20 mmol) EXAMPLE 83-(2-isopropylaminoethoxy)indole hydrochloride3-(Z-dibenzylaminoethoxy)indole (7.1 g), dissolved in a mixture ofethanol (75 ml of 99%) and acetone (25 ml) was hydrogenated in thepresence of palladium/- carbon (2 g of 10%) at -60 psi and 25C for 18hours. The catalyst was filtered off and the filtrate was concentratedin vacuum. The resulting residue was dissolved in isopropanol (30 ml)and converted at 0-5C into the crystalline3-(2-isopropylaminoethoxy)indole hydrochloride (3.45 g) with mp.160-163C. Recrystallization from ethanol (yield: 2.1 g, 45%) raised themp. to l83-185C. Anal. calcd. for C 3H 9ON2C]:

C, 61.3%; H, 7.5%; N, 11.0%; C1, 13.9% Found:

C, 61.3%; H, 7.8%; N, 11.0%; C], 13.9%

EXAMPLE 9 3-(2-cyclohexylaminoethoxy)indole hydrochloride By the sameprocedure as that of Example 8, but substituting cyclohexanone foracetone, 3-( 2 cyclohexylaminoethoxy)indole hydrochloride with mp.225227C was obtained in 42% yield.

EXAMPLE l0 EXAMPLE ll 3-(2-n-butylaminoethoxy)-5-methoxyindole chloride3-(2-aminoethoxy)-5-methoxyindole (5.15g) was dissolved in dry methanol(50 ml), a solution of n butyraldehyde (2.1 g) in dry methanol (10 ml)was added at 05C and the mixture was left at that temperature for 30minutes. Reductive alkylation was performed in the presence ofpalladium/carbon (l of 10%) and hydrogen (50-60 psi) at 25C for 2 hours.The reaction mixture was worked up described in previous examples andyielded 3-(2-n-butylaminoethoxy)indole hydrochloride (3.8 g) with mp.18919 OC. Recrystallization from ethanol (yield: 2.9 g, 39%) raised themp. to l93l94C. Anal. calcd. for C, H O N Cl:

C, 60.3%; H, 7.8%; N, 9.4%;-Cl, 11.9% Found:

C, 60.3%; H, 8.0%; N, 9.5%; Cl, 11.7%

EXAMPLE l2 3-(2-isopropylaminoethoxy)indole hydrochloride In a mannersimilar to that described in Example 10,3-(2-isopropylaminoethoxy)indole hydrochloride with mp. 174l75C wasobtained in 43% yield.

EXAMPLE 13 3-(2-cyclohexylaminoethoxy)-5-methoxyindole hydrochloride Byan analogous procedure 3-(2- cyclohexylaminoethoxy)-5-methoxyindolehydrochlo ride with mp. l92-193C was obtained in 65% yield.

EXAMPLE 14 3-( 2-aminopropoxy )indole hydrochloride hydro- To a solutionof sodium (11 g) in ethanol (260 ml of 99%) was added1-acetyl-3-(2-dibenzylaminopropoxy)indole (39 g). The mixture wasrefluxed for 30 minutes, cooled to about 25C and subsequently treated 5Cinto the crystalline 3-(2-( l-methylbutyl)aminoethoxy) indolehydrochloride (3.5 g) with mp. 189l92C. Recrystallization fromisopropanol (yield: 2.9 g, 51%) raised the mp. to 197l98C.

with ice-water (2.0 L). The resulting emulsion was ex- An l, l d f C HON Cl; tracted with ethyl acetate (3 X 330 ml) and the dried C, 63.7%;H, 8.2%; O, 5.7%; N, 9.9%; Cl, 12.5% ethyl acetate extract wasconcentrated in vacuum. The Found: residue,3-(2-dibenzylaminopropoxy)indole, dissolved C, 63.6%; H, 8.3%; O, 5.8%;N, 9.9%; Cl, 12.6% in ethanol (350 ml of 99%) was h dro enated in thepresence of palladium/carbon (6 g of 1 O%) at 50-60 EXAMPLE 16 psi and25C for 18 hours. After removal of the cata-3-(2-n-butylaminoethoxy)indole hydrochloride. lyst, the solution wasconcentrated in vacuum and the In an analogous procedure,3-(2-n-butylaminoethoxresidue was dissolved in isopropanol (120 ml).Addiy)in hy r h ri wi h mp. l7 l7 was pr tion of a solution of hydrogenchloride in isopropanol pared in 10% yield. at 05C converted the baseinto a crystalline hydrol5 chloride. Recrystallization from isopropanolafforded EXAMPLE l7 3-(2-aminopropoxy)indole hydrochloride. The overall-p y y )ifldolc hydrochlorideyield of 3-(2-aminopropoxy)indolehydrochloride with 3-(2-aminoerhoxyfindole yd o oxaliltC was mp 95 96(jwas 6()% dissolved in methanol (200 ml) at 60C and a solution l 1 foCHHISONzC]; 20 of sodium hydroxide (2.64 g) in methanol (50 ml) was C583 7 61%; O 7 1%; N, 12 4%; 1 155% added.The mixture was allowed tostand at 25C for Found minutes and the precipitated sodium oxalate wasfil- C, 5 0%; H, 9%; O, 72%; N Cl 151% tered off. To the filtrate wasadded n-valcraldehyde To prepare the starting material, a mixture of1-acet- (258 in methanol l at 004C in course ylindoxyl 49 g), 1dibenzylamino 2 oh1oroprooano of 15 mlnutes. The reaction mixture waskept at 0-5C d hl id (130 g) and potassium Carbonate 74 g) for minutesand then subjected to hydrogenation in in dimethylsulfoxide (DMSO) (560ml) was left with the Presence Of Palladium/Carbon g of at stirring at Cfor 12 hours. The reaction mixture was -60 P and for The fy W118 treatedwith ioowator (2,500 m]) and the resulting tered off and the filtrateconcentrated ln vacuum. The omu|sion extracted with chloroform (3 X 250The 30 resulting crystalline residue was partitioned between driedchloroform extract was concentrated in vacuum, ethyl acetate (400 ml)and will (2 X and h i a residue which at room temperature was ethylacetate phase was dried and concentrated in vacl d i a mixture ofethanol 4 parts) and isopropa; uum. The residue was dissolved inisopropanol 160 t 1 part) From this Solution Chilled to 0 5 ml), andaddition of a solution of hydrogen chloride inacetyl-3-(2-dibenzylaminopropoxy)indole (39 g, 34%) 35 lsopropanol at ifollowed y cofflmg with mp. l1l-ll2C, crystallized, forded3-(2-n-pentylammoethoxy) lndole hydrochloride (4.9 g) with mp. l-l6lC.

Recrystallization from ethanol (recovery: 4.1 g, 48% EXAMPLE 5 yield)raised the mp. to l166C. 3-(2-(1-methylbutyl)aminoethoxy)indolehydrochlo- 40 Anal- Caicdfor 15 23 2 i C, 63.7%; H, 8.2%; O, 5.9%; N,9.9%; Cl, 12.5%

3-(Z-dibenzylaminoethoxy)indole (7.1 g), dissolved FOlmdl in a mixtureof ethanol ml of 99%) and methyl n- 36%; H, N, propy] ketone (8 6 was hd d i h pres- In a similar manner, by substituting the appropriate encef ll di b (2 g f 10%) t 50-60 i 45 aldehyde for n-valeraldehyde, thefollowing comand 25C for 18 hours. The catalyst was filtered off and pnd of the gen r l f rm la 1. in which X. Y. R and the filtrate wasconcentrated in vacuum. The residue, R2 are hydrogen, and A is anethylene group. were pre dissolved in isopropanol (20 ml), was convertedat pared:

Example 5 Melting Time for No. R Salt; Yield Point hydroge:

' c nation (hours) 18 CH (CH HCl 40% -171 2 CH 19 clicli HCl 45% 189-1902 l 2o C H CH CH H01 51% 162-163 2 21 CH CH CH llCl 22% 198-4 99 2 22 CH(CH l-lCl 50% 162-163 2 Continued Example 5 Melting Time for No, R SaltYield Point hydroge:

nation (hours) ea" 3\ 23 CHCH CH HCl 55% 181-182 2 CH CH 3 2 2 1 CHCHHCl 45% 1611 .1 65 8 CH CH 25 CH CH Cl-l C IHCH (COOii) 5 1% 180-181 lCH 26 (CH CCH (00010 19% 177-178 6 27 CH (C1-1 HCl 154-155 2 2 CH CH HCl38% 174-175 I 2 a) This compound was purified by recrystallization fromiso:

propanol before converting it to the hydrochloride.

EXAMPLE 29 solution, chilled to 05C, crystallized5,6-dimethoxy-3-(2-isopropylaminoethoxy)indole hydrochloride1-acetyl-3-(2-dibenzylaminoethoxy)-5,6- v dimethoxyindole wasdeacetylated by a procedure analogous to that of Example 1. 3-(2-dibenzy1aminoethoxy)-5,6-dimethoxyindole, isolated as an oil wasconverted to 5,6-dimethoxy-3-(2- isopropylaminoethoxy) indolehydrochloride with. mp. 197-198C by the method described in Example 15.Hydrogenation was complete in 7 hours and the overall yield was 15%.

The starting material, 1-acetyl-3-( 2-dibenzylaminoethoxy)-5,6-dimethoxyindo1e, was prepared in the followingmanner:

6-bromoveratric acid (127 g), prepared by treated veratic acid withbromine in acetic acid, and glycine (71 g) was dissolved in water (725m1) at 40C and pH 10. The reaction was initiated by addition of copperpowder (3.5 g). The pH was maintained at 10 by addition of a sodiumhydroxide solution (6N) and the reaction temperature was kept at 40C bycooling. After 30 minutes the reaction ceased. The reaction mixture,freed of copper powder, was added to chilled hydrochloric acid (1,000 mlof 2 N), yielding N (carboxymethyl)-4,S-dimethoxy-anthranilic acid(114.6 g, 86%) with mp. l81182C.

To a mixture of N-(carboxymethyl)-4,5-dimethoxyanthranilic acid (49 g))in acetic anhydride (300 ml) was added tri-ethylamine (84 ml) withcooling The solution so obtained was kept at C for 1 hour and thenrefluxed for minutes. The reaction mixture was cooled and concentratedin vacuum, leaving a residue which on treatment with ice-water (900 ml)afforded 1,3-diacetyl-5,6-dimethoxyindoxyl. This compound was dissolvedin a refluxing solution of sodium sulfite (60 g) in water (1,000 mi) andethanol (500 m1), and the solution was kept at reflux for 1 /2 hours.The ethanol was distilled off and from the remaining aqueousl-acetyl-5,6-dimethoxyindoxyl (26.4 g. 59% yield) with mp. 238242C. Y v

To a solution ofl-acetyl-S,o-dimethoxyindoxyl (44.7 g) andZ-dibenzylamihoethyl. chloride hydrochloride (84.3 g) in DMSO (1000 'ml)was cautiously added potassium carbonate (117 g). The mixture was leftwith stirring for 9 hours at 60C and for another 9 hours at roomtemperature, followed by treatment with icewater (5,000 ml). Theresulting suspension was extracted with chlorform (2 X 1000 ml) and thechl0roform extract was dried and concentrated in vacuum, leaving aresidue which upon recrystallization from ethanol (275 ml) yielded1-acety|3-( 2- dibenzylaminoethoxy)5,6-dimethoxyindole (45.5 g, 52.3%)with mp. 113115C.

EXAMPLE 30 minutes with a refluxing solution of sodium (6.) g) inethanol(325 ml of 99%). The reaction mixture was chilled and added to ice-water(1,500 ml). The resulting suspension was extracted with ethyl acetate (3X 500. ml) and the extract was dried and concentrated in vacuum. Theresidue, containing 3-(2-(N-bcnzyl-N-nbutylaminoethoxy)indole wasdissolved in ethanol (300 ml of 99%), treated with charcoal (5 g) andsubjected to hydrogenolysis in the presence of palladium/carbon (2 g of10%) for 2 hours at 25C and 50-60 psi. The catalyst was filtered off andthe filtrate concentrated in vacuum. To the residue, dissolved inisopropanol 175 ml) was added hydrogen chloride in isopropanol at 35C.After chilling to 05C, 3-(2n-butylamin.oethoxy)indole hydrochloride(12.4 g, 20?! overall yield) with mp. -171C was obtained.

The intermediate, 1-acetyl-3-(2(N-bcnzyl-N-nbutylamino-ethoxy)indole(mp. 44-45C) was prepared in 36% yield by a procedure analogous to thatdescribed in Example 2.

EXAMPLE 31 3-(2-isopropylaminoethoxy)indole hydrochloride A procedureanalogous to that of the previous example was used for the preparationof 3-(2- isopropylaminoethoxy)-indole hydrochloride with mp. 188189C.The overall yield was 71%. The starting material, 1-acetyl-3-(2-(N-benzyl-N-isopropylamino)ethoxy)indole, was synthesized in thefollowing manner:

l-acetylindoxyl (40.3 g), Z-(N-benzyl-N- isopropylamino)-ethyl chloridehydrochloride (63.0 g) and potassium carbonate (95.3 g) was mixed withDMSO (350 ml). The reaction mixture was kept with stirring at 40C for 18hours and slowly added to icewater (1.4 L), thus affording thecrystalline l-acetyl-3- (2-(N-benzyl-N-isopropylamino)ethoxy)indole(64.7 g) with mp. 5972C. Recrystallization from isopropanol (yield: 49.6g, 62 raised the mp. to 8385C.

EXAMPLE 32 3-(2-isopropylaminopropoxy)indole hydrochloride In a manneranalogous to that described in Example 17,3-(2-isopropylaminopropoxy)indole hydrochloride with mp. 225226C wasprepared in 47% yield.

EXAMPLE 33 3-(2-aminoethoxy)-2-methylindole hydrochloride1-acetyl-3-(Z-dibenzylaminoethoxy)-2- methy1indole( 10.6 g) was treatedwith a refluxing solution of sodium ethoxide, prepared from metallicsodium (2.9 g), inethanol 150 ml of 99%). After cooling to roomtemperature and addition of ice-water (750 ml) the reaction mixture wasextracted with ethyl acetate (2 X 250 ml); extract was dried andconcentrated in vacuum.

The residue, consisting of 3-(2-dibenzylaminoethoxy)-2-methylindole, wasdissolved in ethanol (100 ml of 99%) and subjected to hydrogenolysis inthe presence of palladium/carbon (2 g of 10% at 25C and 50-60 psi for 24hours. The product, freed of catalyst and solvent, was dissolved inisopropanol (40 ml). Addition at O-5C of a solution of hydrogen chloridein isopropanol, followed by ether (200 ml) afforded the crystalline3-(2-aminoethoxy)-2-methylindole hydrochloride (3.5 g) with mp.170-175C. Recrystallization from isopropanol gave the pure compound (2g, 35% yield) with mp. 183184C.

Anal. calcd. for C H ON CI:

C, 58,3%; H, 6.7%; N, 12.4%; C1, 15.6%

Found:

C, 58.2%; H, 6.9%; N, 12.2%; C1, 15.6%

The intermediate, 1-acetyl-3-(2- dibenzylaminoethoxy)-2-methylindole wasprepared in the following manner:

A mixture of 1-acetyl-2-methylindoxyl (37.6 g), 2- (dibenzylamino)ethylchloride hydrochloride (88.2 g) and finely ground potassium carbonate(124.4 g) in DMSO (400 ml) was kept with stirring at 45C for 24 hours.The reaction mixture was added to ice-water (2 L) and extracted withethyl acetate (3 X 500 ml). The extract was dried and concentrated invacuum. When a solution of the residue in isopropanol (150 ml) waschilled slowly to 5C, a crystalline precipitate of 1-acetyl-3-(Z-dibenzylaminoethoxy)-2-methylindole (24 g, 29% yield) withmp. 7880C was obtained. Recrystallization from isopropanol raised themp. to 8283C.

EXAMPLE 34 3-(2-isobutylaminoethoxy)-2-methylindole hydrochloride To asolution in methanol ml) of crude 3-(2- aminoethoxy)-2-methyl indole,prepared from l-acetyl- 3-(Z-dibenzylaminoethoxy)-2-methylindole (12.3g) as described in Example 33, was added a solution of isobutyraldehyde(2.16 g) in methanol (20 ml) and the mixture was kept at 05C for 30minutes. Palladium/- carbon (1 g of 10%) was added and the reactionmixture was hydrogenated at 25C and 50-60 psi for 2 hours. Filtrationfrom the catalyst, followed by evaporation in vacuum of the solvent lefta residue which was dissolved in isopropanol (80 ml). Addition at 05C ofa solution of hydrogen chloride in isopropanol gave the crystalline3-(2-isobutylaminoethoxy)-2-methylindolc hydrochloride (4.1 g) with mp.165C. The pure compound with mp. 1681'69C (3.5 g, 40% yield) wasobtained by recrystallization from isopropanolv Anal. calcd. for C H ONCl:

C, 63.7%; H, 8.2%; N, 9.9%; Cl, 12.5% Found:

C, 63.0%; H, 8.2%; N, 9.8%;C1, 13.0%

EXAM PLE 35 3-( 2-aminoethoxy)-2phenylindole3-(2-dibenzylaminoethoxy)-2-pheny1indole (10 g),

dissolved in a mixture of ethanol (200 ml) and toluene (200 ml) wassubjected to hydrogenolysis in'the presence of palladium/carbon (3 g of10%)at 25C and 'in vacuum of the solvent left a residue of 3-(2-aminoethoxy)-2-phenylindole which was purified by recrystallization fromtoluene. The recrystallized product (2.8 g, 48% yield) had mp. 114-115C.Anal. calcd. for C, H, ON

C, 76.2%; H, 6.4%; N, 11.1%

C, 75.8% H, 6.7%; N, 10.9%

The intermediate. 3-(2-dibenzylaminoethoxy)-2- phenylindole, wasprepared in the following manner:

A mixture of l-acetyl-Z-phenylindoxyl (50 g), 2- dibenzylaminoethylchloride hydrochloride (88.5 g) and finely ground potassium carbonate(124.4 g) in DMSO (400 ml) was left with vigorous stirring at 60C for 5hours. The reaction mixture was added to icewater (2L) and extractedwith ethyl acetate (3 X 500 ml). The extract was dried and concentratedin vacuum. The residue so obtained, consisting of 1-acetyl-3-(2-dibenzylaminoethoxy)-2-phenylindole, was treated for 15 minutes witha refluxing solution of sodium ethoxide, prepared from metallic sodium(23 g), in ethanol (1 L of 99%).

When the reaction mixture was left at 05C the crystalline3-(2-dibenzylaminoethoxy)-2-phenylindole (57 g, 71% yield) with mp.147I49C was obtained.

EXAMPLE 36 3-(2-isobutylaminoethoxy)-2-phenylindole hydrochloride To asolution of crude 3-'(2-aminoethoxy)-2- phenylindole, prepared from 3-(2- dibenzylaminoethoxy)-2-phenylindole (10 g) as described in Example35, in anhydrous. methanol (150 ml) was added in the course of 15minutes at 0-5C a solution of isobutyraldehyde (1.66 g) in methanol (20ml) and the mixture was kept at -5C for 30 minutes. The reaction mixturewas then hydrogenated for 2 hours at room temperature and 5060 psi inthe presence of palladium/carbon (l g of 10%). Filtration from thecatalyst, followed by evaporation in vacuum of the solvent left aresidue which was dissolved in isopropanol (140 ml). Addition at 05C ofasolution of hydrogen chloride in isopropanol yielded 3-(2-isobutylaminoethoxy)-2-phenylindole hydrochloride (3.7 g) with mp.233-235C. Recrystallization from ethanol (yield: 3.1 g, 44%) raised themp. to 236238C. Anal. calcd. for C H ON Cl:

C, 69.6%; H, 7.3%; N, 8.1%; Cl, 10.3% Found:

C, 69.2% H, 7.5%; N, 8.1%; Cl, 10.6%

EXAMPLE 37 3-(2-aminoethoxy)-6-methoxyindole3-(2-dibenzylaminoethoxy)-6-methoxyindole'(15 g), dissolved in ethanol(350 ml of 99%),was subjected to hydrogenolysis in the presence ofpalladium/carbon (5g of at 25C and 50-60 psi for 7 hours.

Filtration from the catalyst, followed by evaporation in vacuum of thesolvent left a crystalline residue (7g) containing3-(Z-aminoethoxy)-6-methoxyindole. A fraction (2 g) of this residue,recrystallized from isopropanol, yielded the pure compound (0.6 g, 26%)with mp. 129132C. The remainder (5 g) was used in the following Example38. Anal. Calcd. for C111! u Qg Ngi C, 64.1%; H, 6.7%; N, 13.6% Found:

The starting material, 3-(Z-dibenzylaminoethoxy)-6- methoxyindole, wasprepared in the following manner:

A mixture of l-acetyl-6-methoxyindoxyl (28.7 g), 2- dibenzylaminoethylchloride hydrochloride (62.0 g) and finely ground potassium carbonate(87.0 'g) in DMSO (275 ml) was stirred vigorously at 40C for 18 hours.The reaction mixture was added to ice-water (1,250 ml) and extractedwith ethyl acetate (4 X 300 ml). The extract was dried and the solventwas evaporated in vacuum, leaving a residue which was recrystallizedfrom a mixture of ethanol (150 ml) and ethyl acetate (50 ml). Thecompound 1-acetyl-3-(2- dibenzylaminoethoxy)6-methoxyindole with mp.9697C (21 g, 35% yield) so obtained was dissolved in ethanol (275 ml of99%) containing sodium ethoxide prepared in situ from metallic sodium(5.5 g). Refluxing the solution for minutes followed by chilling to 05Cyielded the crystalline 3-(2- dibenzylaminoethyl)-6-methoxyindole (16.5g, 87%) with mp. 83-84C.

EXAMPLE 38 3-(2-isobutylaminoethoxy)-6-methoxyindole hydrogen oxalateThe crude 3-(2-aminoethoxy)-6-methoxyindole (5 g), prepared in Example37 above, was subjected to a reductive alkylation with isobutyraldehydein a manner analogous to that described in Example 36, followed byfiltration and evaporation of the solvent. A chilled solution of theresidue in ethanol (90 ml of 99%) was added at 05C in the course ofminutes to a solution of oxalic acid (6.3 g) in ethanol (50 ml) and themixture was left for 30 minutes at the same temperature. The crystalline3-(2-isobutylaminoethoxy)-6- methoxyindole hydrogen oxalate was isolatedand recrystallized from aqueous ethanol The pure' compound (2.7 g, 32%)has mp. -161C. Anal. calcd. for C H O N C, 57.9%; H, 6.9%; N, 10.0%Found:

C, 56.9%; H, 6.7%; N, 7.8%

EXAMPLE 39 3-(2-aminoethoxy)-4-methoxyindole3-(2-dibenzylaminoethoxy)-4-methoxyindole (17 g), dissolved in ethanol(550 ml of 99%) was hydrogenolysed in the presence of palladium/carbon(5 g of 10%) at 25C and 50-60 psi in the course of 26 hours. Filtrationfrom the catalyst, followed by evaporation in vacuum of the solvent lefta residue (9.2 g). One half of this residue was recrystallized fromisopropanol. yielding 3-(2-aminoethoxy)-4-methoxyindole (275g, 55%yield) with mp. 146l 50C. The other half of the residue was used in thefollowing Example 40. Anal. calcd. for C H N O C, 64.1%; H, 6.9%; N,13.6% Found:

C, 64.3%; H, 7.0%; N, 13.5%

The intermediate, methoxyindole, was prepared-in the following manner:

To a solution of 6-methoxyanthranilic acid (46.5 g) and sodium hydroxide(23.6 g) in water (100 ml) was added a solution of chloracetic acid(26.5 g) and sodium carbonate (18 g) in water (50 ml). After heating to50C for 6 hours, a solution ofchloracetic acid (13.2 g), sodiumhydroxide (6 g) and sodium carbonate (8.5

g) in water (25 ml) was added and heating was continued. The sameaddition was repeated after 12 hours, the reaction mixture was left at50C for further 10 hours, cooled and added slowly and with vigorousstirring to hydrochloric acid (275 ml of 4 N). N-carboxymethyl-6methoxyanthranilic acid (36.1 g, 57%) with mp. -186C wasisolated.-

Triethylamine (52.5 ml) was added at room temperature to a solution ofNcarboxymethyl-6- methoxyanthranilic acid (31.5 g) in acetic anhydrideml). The reaction mixture was kept at 25C for 1 hour and then heated toreflux temperature for an additional period of 30 minutes, followed byevaporation of the solvent. After treatment of the residue with icewater(750 ml), the crystalline 1,3-diacetyl-4- methoxyindoxyl (31.1 g) withmp. l45148C was obtained.

A solution of 1,3-diacetyl-4-methoxyindoxyl (31.1 g) in ethanol (800 mlof 96%) was added to a solution of sodium sulfite (44 g) in water (800ml) at 50C and the reaction mixture was kept at that temperature for 2hours. Ethanol was stripped off and, after cooling,l-acetyl-4-methoxyindoxyl with mp. 145l46C 18.5 g, 65% yield) wasobtained from the remaining aqueous solution.

A mixture of l acetyl-4-methoxyindoxyl (13.1 g), 2- dibenzyl aminoethylchloride hydrochloride (26.6 g) and potassium carbonate (33.2 g) in DMSO(125 ml) was stirred vigorously at 40C for 18 hours. lee-water (800 ml)was added and the mixture was extracted with ethyl acetate (3 X 200 ml).The reaction product was worked up in the usual manner andrecrystallized from isopropanol, yielding 1 -acetyl-3-( 2- 3-(2-dibenzylaminoeth0Xy)-4- dibenzylaminoethoxy)-4-methoxyindole (15 g,58%

' yield) with mp. 125126C.

EXAMPLE 40 3-(2-isobutylaminoethoxy)-4-methoxyindole hydrogen oxalate Toa solution in methanol (100 ml) of the crude 3-(2aminoethoxy)-4-methoxyindole (4.6 g), prepared in Example 39 above, wasadded isobutyraldehyde (3.2 g) and a molecular sieve g of type 3A) andthe reaction mixture was left at 25C with stirring for 2 hours.

Sodium borohydride (1.7 g) was added portionwise in the course of 10minutes and after additional 1 hour at 25C the molecular sieve wasfiltered off, and the solvent evaporated in vacuum. The residue waspartitioned between water (2 X 150 ml) and ethyl acetate (200 ml), theethyl acetate phase was dried and concentrated in vacuum.

A solution of the residue in ethanol (25 ml of 99%) was added at 25C toa solution of oxalic acid (6.0 g) in ethanol (50 ml of 99%). Chilling ofthe suspension to 05 C yielded the crystalline 3-( 2-isobutylaminoethoxy)-4-methoxyindole hydrogen oxalate (3.9 g).Recrystallization from aqueous ethanol (80%) yielded the pure compound(2.9 g, 51% yield) with mp. ll52C.

Anal. calcd. for C17H24N2O6, H20:

C, 55.1%; H, 7.1%; N, 7.6% Found:

C, 55.4%; H, 7.2%; N, 7.8%

EXAMPLE 41 3-(2-isopropylaminoethoxy)-4-methoxyindole chloride In amanner analogous to that described in Example 8,3-(2-isopropylaminoethoxy)-4-methoxyindole hydrochloride with mp.216-218C was obtained in 477 yield.

hydro- EXAMPLE 42 EXAMPLE 43 3-(2-ethylaminoethoxy)-2-pheny1indolehydrochloride Starting from l-acetyl-2-pheny1indole, 3-(2-ethylaminoethoxy)-2-phenylindo1e hydrochloride with mp. 257-259C wasprepared using procedures analogous to those described in example 31. Inthis example debenzylation was complete after 24 hours and the catalysthad to be exchanged after 8 hours. The overall yeild was 35%.

EXAMPLE 44 3-(2-isopropylaminoethoxy)-2-pheny1indole chloride3-(2-dibenzylaminoethoxy)-2-phcnylindole was converted to3-(2-isopropylaminoethoxy)-2-phenylindole hydrochloride with mp.207-208C by the method described in Example 8. The reaction wasperformed in toluene instead of ethanol. The yield was 45%.

EXAMPLE 45 3-(2-aminoethoxy)-2-benzylindole2-benzyl-3-(Z-dibenzylaminoethoxy)indole (4.66 g), dissolvedin a mixtureof toluene (50 ml) and ethanol (50 ml) was hydrogenolyzed in thepresence of palladium/carbon (3 g of 10%) at 50-60 psi and 25C in thecourse of about 60 hours. The. catalyst was filtered off and thefiltrate concentrated in vacuum. The residue was recrystallized from a1:1 mixture of isooctane and ethyl acetate, affording3-(2-aminoethoxy)-2- benzylindole (0.80 g, 29% yield) with mp. 1l31 14C.Anal. calcd. for C H N O:

C, 76.7%; H, 6.8%; N, 10.5%

Found:

C, 76.3%; H, 6.6%; N, 10.4% The starting material, 2-benzyl-3-(2-dibenzylaminoethoxy) indole, was prepared in the following manner:

o-chlorobenzoic acid (156.6 g) and phenylalanine (289 g) were heated toreflux in water 1.5 L) at pH 9. Cuprous oxide (4 g) was added, and thepH was maintained at pH 9 by addition of a sodium hydroxide solution (6N) while the reaction mixture was kept under reflux for 8 hours. After 3hours a further portion of cuprous oxide (4 g) was added. The reactionmixture, freed ofinsoluble salts, was added to chilled hydrochlo ricacid (800 m1 of 6 N), yielding N-(1-carboxy-2- phenylethy1)anthranilicacid (204 g, 72%) with mp. 140C.

To a mixture of N-( 1-carboxy-2-phenylethyl)anthranilic acid (173 g) andacetic anhydride (900 ml) was added triethylamine ml) with cooling. Thesolution so obtained was kept at 25C for 2 hours and refluxed for 30minutes. The reaction mixture was cooled andconcentrated in vacuum,leaving a residue which on treatment with ice-water (3 L) afforded2-benzyl-1,3-diacetylindoxyl. A solution of this compound in ethanol(1.8 L) was added to a refluxing solution of sodium sulfite (184 g) inwater (2.8 L). and reflux was continued for a further 1 /2 hours. Fromthe re action mixture, cooled to 20C, l-acetyl-Z-henzylindoxyl (71 g,45% yield) with mp. l15-117C crystallized.

To a mixture of 1-acetyl-2-benzylindoxyl (71 g), 2- (dibenzylamino)ethylchloride hydrochloride (118 g) in DMSO (670 ml) was cautiously addedpotassium carbonate (147 g). The reaction mixture was left with stirringfor 18 hours at 50C, and then treated with icewater (3.5 L). Theresulting emulsion was extracted with ethyl acetate (3 X 750 ml), andthe ethyl acetate extract was dried and concentrated in vacuum. leaving1-acetyl-2-benzyl-3-(ZdibenZyIaminoethoXy)indolc as an oil. Thiscompound was treated for 30 minutes with a refluxing solution of sodiumethoxidc, prepared from sodium (18.5 g) in ethanol (1.4 L, 99%). Thereaction hydro mixture was cooled to l20C and added to water (6.5 L).The resulting emulsion was extracted with ethyl acetate (3 X 1 L) andthe ethyl acetate was dried and concentrated in vacuum, leaving aresidue, which after recrystallization from a mixture of isooctane (1.8L) and benzene (0.6 L) yielded 2benzyl-3-(2- dibenzylaminoethoxy)indole(43 g) with mp. 9698C. The over-all yield was 36%.

EXAMPLE 46 hydroisopropylaminoethoxy)indole hydrochloride (9.9 g)v withmp. 204205C. Recrystallization from ethanol raised the mp. to 211C. Theyield was 5.8g(40%). Anal. calcd. for C H C1 N 0:

C, 69.6%; H, 7.3%; CI, 10.3%; N, 8.1% Found:

C, 69.6%; H, 7.3%; Cl, 10.5%; N, 8.1%

EXAMPLE 47 l-ben2yl-3-( 2-isopropylaminoethoxy)indole chloridel-acetyl-3-( 2-( N-benzyl-N-isopropylamino )ethoxy)indole (59.5 g) wasdeacetylated by the procedure described in Example 30.

The crude 3-(2-(N-benzyl-N-isopropylamino)ethoxy)indole was dissolved indimethylformamide, DMF, (500 ml) and the solution was concentrated invacuum.

hydro- The residue dissolved in DMF (500 ml) was added in the course of15 minutes at 25C to a stirred suspension of sodium hydride (8.6 g of a50% suspension in mineral oil) in DMF (250 ml). The reaction mixture wasleft with stirring at 25C for 2 hours and benzyl chloride (22.8 g)dissolved in DMF (30 ml) was added in the course of 15 minutes. Thereaction mixture was kept at 25C for another hour and then poured intoiee-water (5 L). The resulting emulsion was extracted with ethyl acetate(3 X 750 ml) and the ethyl acetate extract was concentrated in vacuum.The residue containing 1-benzyl-3-(2-(N-benzyl-N-isopropylamino)ethoxy)indole was dissolved inethanol (400 ml of 99%), treated with charcoal (7 g) and then subjectedto hydrogenolysis in the presence of palladium/carbon (10 g of 10%) at50-60 psi and 25C for 10 hours. The catalyst was filtered off and to thefiltrate, concentrated in vacuum to about 200 ml, was added a solutionof hydrogen.

chloride at 60C. After chilling to 0-5C, 1-benzyl-3-(2-isopropylaminoethoxy)indole hydrochloride (36 g, 61% over-all yield)with mp. 19920()C was obtained. Anal. calcd. for C H Cl N 0:

C, 69.6%; H, 7.3%;C1, 10.3%; N, 8.1% Found:

C, 69.8%; H, 7.2%; Cl, 10.4%; N, 8.3%

EXAMPLE 48 1-benzyl-3-( 2-isopropylaminoethoxy )-2-phenylindolehydrochloride 3-( 2-(N-benzyl-N-isopropylamino)ethoxy-2-3-(Z-isopropylaminoethoxy)-4-methoxyindole hydrophenylindole (28.3 g)was converted to 1-benzyl-3-(2-(N-benzyl-N-isopropylamino)ethoxy)-2-phenylindolc by a procedureanalogous to that of the previous example. The latter compound,recrystallized from ethanol, was dissolved in toluene ml) and ethanol(240 ml) and hydrogenolyzed in the presence of palladium/carbon (4 g of10%) at 25C and 50-60 psi for 5 hours. The catalyst was filtered off andthe filtrate concentrated in vacuum. To the residue, dissolved inisopropanol, was added a solution of hydrogen chloride in isopropanol at05C, and 1-bcnzyl-3-(2- isopropylaminoethoxy)-2-phenylindolehydrochloride (26.8 g) with mp. l88-l 89C was obtained.Recrystallization from ethanol raised the mp. to 193C The over-all yieldwas 22.7 g (73%). Anal. calcd. for C H- CI N 0:

C, 74.2%; H, 7.0%; Cl, 8.4%; N, 6.7%

Found:

C, 74.0%; H, 7.0 CI, 8.4%; N, 6.7% The starting material,B-(Z-(N-benZyI-N- isopropylamino) ethoxy)-2-phenylindole with mp. l l2l14C, was prepared in the manner described in Example 31. The yield was79% starting from l-acetyl- Z-phenylindole.

EXAMPLE49 chloride In a manner similar to that described in Example 30,3-(2-isopropylaminoethoxy)-4-methoxyindole' hydrochloride with mp. 218Cwas prepared in 69% yield.

The starting material, 1-acetyl-3-(Z-(N-benzyl-N-isopropylamino)eth0xy)-4-m ethoxyindole, was prepared in the followingmanner:

To a mixture of 1-acetyl-4-methoxyindoxyl (15.3 g) and2-(N-benzyl-N-isopropylamino)ethyl chloride hydrochloride (27.9g) inDMSO ml) was cautiously added potassium carbonate (41.5 g). The reactionmixture was left with stirring for 18 hours at'50C and then poured intoice-water (600 ml). The resulting emulsion was extracted with ethylacetate (3 X 200 ml), and the extract was dried and concentrated invacuum. The residue so obtained yielded, after trituration withisopropanol, l-acetyl-3-(2'(N-benzyl-N-isopropylamino)ethoxy)-4-methoxyindole (24 g, 74%) with mp. 104-105C.

EXAMPLE50 in isopropanol at 2()30C. After chilling to 0-5C,

l-benzyl-3-(2-isopropylaminoethoxy)-4- methoxyindole hydrochloride (15.4'g) with mp. l8l-183C was obtained. The over-all yield was 80%.

Anal. calcd. for C H Cl N C, 67.3%; H, 7.3%; Cl, 9.5%; N, 7.5%

I Found:

i 1-benzyl-3-(2-isopropylaminoethoxy)-2-methylindole hydrochloride Amixture of 1-acetyl-2-methylindoxyl (25.5 g), 2-(N-benzyl-N-isopropylamino)ethyl chloride hydrochloride (50.5 g) andpotassium carbonate (74.5 g) in DMSO (250 ml) was kept with stirring at50C for 10 hours. The reaction mixture was worked up as described inExample 45, affording 1-acetyl-3-(2-(N-benzyl-N-isopropylamino)ethoxy)-2-methylindole, which was converted to1-benzyl-3-(2(N-benzyl-N- isopropylamino)ethoxy)-2-methylindole byprocedure analogous to those described in Example 47. The lattercompound, isolated as an oil, was dissolved in ethanol (250 ml of 99%),treated with charcoal (5 g) and bydrogenolyzed in the presence ofpalladium/carbon (5 g of at 50-60 psi and 25C for 24 hours. The catalystwas replaced by a fresh portion (3 g) and hydrogenolysis was continuedfor an addition period of 6 hours. The reaction mixture was worked up asdescribed in the previous example and yielded, after recrystallizationfrom isopropanol, 1-benzyl-3 -(2- isopropylaminoethoxy)-2-methylindolehydrochloride (9.6 g, 40% over-all yield) with mp. 169*170C. Anal.calcd. for C H Cl N 0:

C, 70.3%; H, 7.6%; C1, 9.9%; N, 7.8% Found:

C, 70.2%; H, 7.5%; Cl, 10.1%;N, 7.7%

EXAMPLE 52 1--q-butyl-3-(2-isopropylaminoethoxy)indole chloride 3-( 2-(N-benzyl-N-isopropylamino )ethoxy )indole g) was alkylated with n-butylbromide by the procedure described in Example 47. The product, 3-(2-(N-benzyl-N-isopropylamino)ethoxy)-l-n-butylindole, isolated as an oil,was dissolved in a mixture of toluene (100 ml) and ethanol (100 ml of99%), treated with charcoal (3 g) and hydrogenolyzed in the presence ofpalladium/carbon (3 g of 10%) at 50-60 psi and C for 13 hours. Thecatalyst was filtered off and the filtrate concentrated in vacuum. Theresidue was dissolved in isopropanol, and to the solution was added asolution of hydrogen chloride in isopropanol at 20-30C. After chillingto 0-5C, 1-n-butyl-3-(2- isopropylaminoethoxy)indole hydrochloride (11.9g) with mp. 143144C was obtained. Recrystallization from isopropanolafforded 10.3 g of the compound with mp. 143-144C. The over-all yieldwas 50%. Anal. calcd. for C H Cl N 0:

C, 65.7%; H, 8.8%; Cl, 11.4%; N, 9.0% Found:

C, 65.8%; H, 8.5%; C1, 11.5%; N, 9.0%

hydro- EXAMPLE 53 1-benzyl-3-(2-isopropylaminoethoxy)-5- methoxyindolehydrochloride l-acetyl-3-(2-(N-benzyl-N-isopropylamino)ethoxy)-S-methoxyindole (50.5 g) was converted to 1-benzyl-3-(2-(N-benzyl-N-isopropylamino)ethoxy)-5- methoxyindole as described inExample 47. The latter compound was subjected to hydrogenolysis for 3hours by the procedure described in the previous example, yielding1-benzyl-3-( 2-isopropylaminoethoxy)-5- methoxyindole hydrochloride(33.4 g, over-all yield with mp. 144-l45C. Anal. calcd. for C H Cl N 0:

C, 67.3%; H, 7.3%; Cl, 9.5%; N, 7.5% Found:

C, 67.6 H, 7.3%; Cl, 9.6%; N, 7.5%

The starting material, l-acetyl-3-(2-(N-benzyl-N-isopropylamino)ethoxy)-5-methoxyind0le with mp. 108110C was prepared inyield in a manner analogous to that described in Example 49. Thereaction time was 10 hours.

EXAMPLE 54 methylindole hydrochloride (10g) was treated with asolutionof sodium hydroxide (50 ml of l N) and the resulting emulsion wasextracted with chloroform (2 X 50 ml). The chloroform extract was driedand concentrated in vacuum. The residue dissolved in ethanol (200 ml of99%) was hydrogenolized in the presence of palladium/carbon (3 g of 10%)at 5060 psi and 25C for 1018 hours. The reaction mixture worked up asdescribed in Example 52, yielded 3-(2-aminoethoxy)-5-methoxy-l-methylindole hydrochloride (3.5 g, 59%) with mp. l57158C.Anal. calcd. for C H Cl N 0 C, 56.2%; H, 6.7%; CI, 13.8%; N, 10.9%; 0,12.5%

Found:

C, 56.1%; H, 6.7%; Cl, 13.7%; N,-l0.8%; O, 12.7%

3-(2-dibenzylaminoethoxy)-5-methoxy-1- methylindole hydrochloride withmp. 177-l78C was prepared as described in Example 47. The yield was 65%.

EXAMPLE 55 and the salts thereof with physiologically acceptable acids,in which each ofX and Y is selected from the group consisting ofhydrogen, hydroxy, lower alkyl having l3 carbon atoms and lower alkoxyhaving l-3 carbon atoms,

R is selected from the group consisting of hydrogen; lower alkyl havingl4 carbon atoms and henzyl,

25 I 26 R is selected from the group consisting of hydrogen, 6, Acompound according to claim 1, namely, 1-

lower alkyl having l4 carbon atoms, benzyl andbenZyl-3-(Z-isoprgpylaminoethoxy) ind phenyl, hydrochloride, R selectedfrom the group consistlng of hydrogen, 5 7. A Compound according toclaim 1, namely,

lower alkyl having 1-8 carbon atoms, cycloalkyl benzyl 3(zisopropylaminoethoxy) indo1c having 5 or 6 carbon atoms, benzyl and 2-hydrochloride 1 phenylethyl, and

Aisastraight or branched alkylene chain containing A compound accordingto claim namely L benzyl-3-(2-isopropylaminoethoxy)Z-phenyI-indolc from2 to 4 carbon atoms. 10 h drochloride 2. The hydrochloride of a compoundaccording to y claim 1 9. A compound according to claim 1, namely, 1-

benzyl-3-( 2isopropylaminoeth0xy )-4-methoxy- 3. The oxalate of aderivative according to claim 1.

indolehydrochloride.

4. A compound according to claim 1, namely, 3-(2-isopropylaminoethoxy)-indole-hydrochloride. 10. A compound according toclaim 1, namely, 1-

5. A compound according to claim 1, namely, 3-(2-benzyl-3-(2-isopropylaminoethoxy)-5-mcthoxyisopropylaminoethoxy)-4-methoxy-indoleindolehydrochloride.hydrochloride.

UNITED STATE PATENT OFFICE CERTIFICATE OF CCRRECTTCN PATENT NO. 13,860,609 DATED J u ry 1 1975 INVENTOR(S) Behrend Friedrich Lundt It iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below;

On the caption page, at [75], "Lyngby" should read --Srz$borg 3n thecaption page, at [63], "May 20, 1970." should read November 23, l97l-- 4On the caption page at [30], "May 27, 1970" should read -May 27, 1969--In the specification: Jolum'n 1, lines .5-6, "May 20, 1970" should read--November 23, l97l- Column 1, line 6 "R should read --R Column l, line30, "ED should read -LD Column l, lines 50-51, "propounced" should read--pronounced-- Jolumn l, Table I, third line from bottom of page "lhydrochloride" should read -hydrochloride- Column 5, Table I, fourthline from end of Table "hydrochloride 52" should read -hydrochloride-.The number "52" should appear in the "Anti-inflammatory. column. Column5, Table II, sixth line of table, "-isopropylaminoethoxy)5" should read-iso',..-ropylaminoethoxy)-5- Column 7, Example 2, second line, "-5-"should read )-5 Column 8 Example line 32, )-5" sho ld d 5 Column 12,Example 17, line ll, O, 5 9%" should read -O, 5 7%- Column 13, Example29, line 45, "treated" should read treating- Column 13, Example 29, lineU6, "veratic" should read --veratrio-- Jolumn. 15, Example 33, line 12"10%" should read lO%)- Column 15, "Example 33, line 52, "58,3%" shouldread 58 .3%--

Column 16, Example 35, lines il- 42, "C, 75. 8% H," should read---Found: C, 75.8%; H, Column 17, Example 37, line 5,"dibenzylaminoethyl" should read -dibenzylaminoethoxy- Column 18,Example 39, line 21, "1 16-150" should read l 47-l50- Column 2 1, line17, "We claim" should read -I claim Column 25, Claim 3, "derivative"should read --compound Signed and Sealed this fourteenth Day Of October1975 [SEAL] A ttest:

RUTH C. MASON C. MARSHALL DANN Arresting ()ffrcer Commissioner ofPaIentsand Trademarks

2. The hydrochloride of a compound according to claim
 1. 3. The oxalateof a derivative according to claim
 1. 4. A compound according to claim1, namely, 3-(2-isopropylaminoethoxy)-indole-hydrochloride.
 5. Acompound according to claim 1, namely,3-(2-isopropylaminoethoxy)-4-methoxy-indole-hydrochloride.
 6. A compoundaccording to claim 1, namely,1-benzyl-3-(2-isopropylaminoethoxy)-indole-hydrochloride.
 7. A compoundaccording to claim 1, namely,1-benzyl-3-(2-isopropylaminoethoxy)-indole-hydrochloride.
 8. A compoundaccording to claim 1, namely,1-benzyl-3-(2-isopropylaminoethoxy)-2-phenyl-indole hydrochloride.
 9. Acompound according to claim 1, namely,1-benzyl-3-(2-isopropylaminoethoxy)-4-methoxy-indolehydrochloride.
 10. Acompound according to claim 1, namely,1-benzyl-3-(2-isopropylaminoethoxy)-5-methoxy-indolehydrochloride.